A news breaking story by Bruce Seeman of Newhouse News (excerpts below) reveals a major systemic breakdown in medical ethics–“there’s something rotten in the state of [biomedical research].”

Complaints about a lung disease air ventilation study conducted by the prestigious ARDS Network has raised serious concerns about whether the lives of critically ill patients recruited at 40 hospitals, (mostly) without their informed consent, were put at “increased risk of death.”

The patients in three ARDS studies were subjected to two extreme experimental treatments. Scientists not affiliated with the ARDS Network ask, criticize the ARDS studies for failing to provide study patients with the best current standard of care. (See: http://ajrccm.atsjournals.org).

Newhouse News reports that federal authorities (Office of Human Research Protections, OHRP) “have taken the extraordinary step of demanding that a prominent group of doctors turn over treatment data for about 1,800 study subjects at more than 40 hospitals nationwide.” The ARDS Network is comprised of 20 prestigious research institutions and 40 participating hospitals. In 2000 ARDS investigators had reported significant findings about improved survival rates for critically ill patients with acute respiratory distress syndrome, using an experimental method of air ventilation. Those findings, however, and the methods by which the investigators arrived at their conclusions, are in dispute. http://www.ahrp.org/ethical/Koski0729.php

An examination of patient records is necessary for establishing whether patients who were not in the ARDS study had better or worse survival rates.

According to Dr. Gordon Bernard of Vanderbilt University, the lead research institution, the 3 ARDS experiments cost taxpayers $30 million. Though approved by ALL 40 institutional review boards, OHRP found that ALL informed consent documents at ALL participating ARDS institutions violated federal requirements under 45 CFR 46: See: http://www.ahrp.org/ethical/CaromeARDS082802.php

The ARDS experiments reveal a fundamental moral conflict between current research practice and the physician’s ethical, scientific, and legal obligation toward patients (subjects). The following moral imperatives are not options:

“First, do no harm” [known as, the Hippocratic Oath]; “The voluntary consent of the human subject is absolutely essential.” [Nuremberg Code] "the benefits, risks, burdens and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic, and therapeutic methods." [Declaration of Helsinki]

Some influential scientists seem to disagree. They believe that they have a right to determine whether ethical standards can be circumvented for the greater good of science. Such moral decisions, however, are not for scientists alone to make.

WASHINGTON – Concerned that hundreds of hospital patients with failing lungs were placed at "increased risk of death” by a series of clinical trials, federal investigators have taken the extraordinary step of demanding that a prominent group of doctors turn over treatment data for about 1,800 study subjects at more than 40 hospitals nationwide.

The Office for Human Research Protections, the government’s lead watchdog over such studies, called for the records in a 29-page letter suggesting that research physicians may have designed flawed experiments, failed to explain risks to critically ill patients or their families, and given some patients harmful treatment.

According to the letter, federal investigators have unearthed "serious unresolved concerns” that the trials failed to comply with federal regulations aimed at protecting human subjects.

The three trials in question – two completed, one put on hold in light of the controversy – were conducted by a national network of researchers affiliated with 20 institutions, mostly major universities. They tested therapies for acute respiratory distress syndrome, or ARDS, a lethal inflammatory lung condition.

The researchers’ designated spokesman, Dr. Gordon Bernard of Vanderbilt University, defended their work as ground-breaking science that will save lives.

Bernard, who estimated that more than $30 million in federal funds has been spent on the studies, said he expected researchers to comply with the call for patient data. But he said the regulators are being overzealous and warned that their criticisms, if upheld, will not only scuttle the lung trials but "cripple” a broad category of biomedical experiments of similar research design. …cut….

The research group, known as the ARDSNetwork, was assembled in 1994 and funds its work through contracts with the National Heart, Lung and Blood Institute, part of the federal government’s National Institutes of Health. In addition to Vanderbilt and Massachusetts General, the 20 institutions represented in the group include the Cleveland Clinic, Johns Hopkins University, the University of Pennsylvania, the University of Michigan, Louisiana State Health Sciences Center and Baystate Medical Center in Springfield, Mass.

ARDS is a rapidly progressing lung condition that often piggybacks on other illnesses. About one in three patients develops ARDS as a result of sepsis, a bodywide infection. But ARDS may also occur within 24 to 48 hours of a lung injury or onset of a disease such as pneumonia. The syndrome has largely baffled doctors and kills about one in three of the 150,000 people afflicted each year.

In ARDS patients, life-threatening conditions emerge when blood and fluid leak into the lungs’ tiny air sacs. Patients become short of breath, and doctors may hear crackling or wheezing sounds in the lungs. …cut…

With decreased oxygen delivery to body tissue, the skin may become blue. The heart, brain or other organs may malfunction. Complications such as kidney failure may occur immediately or weeks later.

Patients with ARDS, often heavily sedated and in intensive care, receive a complex menu of treatments that includes breathing via a mechanical ventilator, manipulation of lung pressures and fluid therapy. Experimental therapies in these three areas were studied in the three ARDSNetwork trials. One of the tests resulted in a landmark finding that the controversy has now called into question.

The Oct. 7 demand for patient information was written by Dr. Michael Carome, director of compliance oversight at the OHRP, an independent agency under the secretary of Health and Human Services.

Federal officials have refused to release the letter, citing its relevance to an ongoing investigation. Carome declined to be interviewed for the same reason. The document was obtained from another source by Newhouse News Service.

Given the lethal nature of ARDS, hundreds of patients were expected to die during the studies. And hundreds did – more than 300 in one study.

The question posed by regulators is whether there were more deaths than would occur normally, and whether any increase was caused by the studies’ design. "Groups of experimental subjects … may have been placed at an increased risk of death” in comparison to patients given standard care, the OHRP letter said.

The letter was addressed to administrative officials at three institutions with leading roles in the ARDSNetwork research – the Cleveland Clinic, Vanderbilt and Massachusetts General.

While seeking patient information from the three ARDSNetwork studies, Carome asked the institutions to investigate numerous concerns. Among them:

– Researchers appeared to have conducted studies that didn’t include an appropriate control group, OHRP said, a mistake that might have compromised scientific findings and put patients at higher risk.

A control group is established for purposes of comparison. It contains patients whose treatment represents current standard care, thereby allowing researchers to compare experimental therapies. If the control group does not represent current standard care, some experts say, the results of the experiment are scientifically flimsy and shouldn’t be applied to everyday medical practice.

In the ARDSNetwork studies, Carome said, patient risk may have increased for control patients who didn’t get standard care. An inappropriate control also would have made it difficult for researchers to contrast death rates in experimental groups against what occurs normally.

In other words, OHRP wrote, "Any increased risk of death … may have gone undetected.”

…cut…

OHRP said the ARDSNetwork protocols lacked justifications for allowing family members to provide consent – most patients were heavily sedated – particularly when studies carried "greater than minimal risks” and "possibly limited benefits.”

Protocols did not describe additional safeguards that could have protected study candidates "vulnerable to coercion” given their dire condition and their families’ distress, the government letter said.

The inquiry into the ARDSNetwork studies began after a 1996-99 study published May 4, 2000, in the prestigious New England Journal of Medicine. That clinical trial, which studied 861 patients on mechanical ventilation, concluded that patients receiving small breaths from a ventilator had a lower death rate – 31 percent versus 40 percent for those receiving large breaths.

The conclusion was hailed by officials at NIH, and new guidelines for treating ARDS patients were widely distributed among intensive care doctors.

After the results were published, however, an anonymous letter to federal regulators attacked the study and sparked the investigation that now spans two and a half years.

The letter writer asked regulators to investigate whether researchers had properly gained patient consent. Carome and five other OHRP investigators conducted inquiries of 10 study sites. Nine of those investigations were completed this year. Investigative summaries by OHRP said study centers had provided legal justifications for gaining consent through surrogates, but that in some cases consent forms did not fully outline patient risks.

Last month, five NIH scientists published an analysis asserting that the ARDSNetwork ventilator study was flawed. The results were irrelevant, the critics said, because the test appeared to compare patients getting the experimental small-breath therapy to a control group that represented a false standard.

"Overall, this study design may have resulted in substantial numbers of control patients receiving inferior treatment,” according to the paper published in the American Journal of Respiratory and Critical Care Medicine.

In an interview, Bernard, the ARDSNetwork spokesman, called the critical analysis "phony” and "worthless.”

NIH Senior Researchers Drs. Peter Q. Eichacker and Charles Natanson, the lead authors of the critical paper, have declined to publicly discuss the issue.

Mindful of the controversy, NIH suspended the ARDSNetwork fluid therapy study, which was of similar design, and appointed a panel in August to review the work. The panel’s membership and its analyses have not been made public, but an NIH news release said the group judged the suspended study "well designed, safe and important.”

In September, Bernard predicted the suspended study would resume within days. It has remained suspended, however, while OHRP continues its investigation.

The October OHRP letter, while summarizing concerns about ARDSNetwork studies, is most notable for directing institutional administrators to turn over data from three categories of hospital patients – those treated before the studies began, those who were invited to join the studies but declined, and those who enrolled.

Carome would not discuss why OHRP seeks the data. But experts on both sides of the controversy said regulators clearly want to get closer to answering a fundamental question: Did researchers test experimental therapies against valid control groups?

Vera Hassner Sharav, president of the Alliance for Human Research Protection, a patient advocacy group, lauded the OHRP investigation. Sharav said flatly that the ARDSNetwork researchers compromised patient safety in their study of ventilation management.

"They compared two extreme treatments procedures and denied patients the best currently available treatments,” said Sharav, who in July wrote a complaint letter to OHRP about the ARDSNetwork. "That’s outrageous.”

Bernard dismissed Sharav’s allegations, saying the ventilator study was safe, approved by numerous review panels and yielded results that will help doctors save thousands of lives.

"If she knew anything about clinical trials and statistics, she wouldn’t say what she’s saying,” Bernard said of Sharav. "I think it’s a reflection of naivete.”